At a Glance

Congenital adrenal hyperplasia (CAH) includes a group of autosomal recessive disorders that lead to a deficiency in the steroid synthesis pathway for aldosterone and/or cortisol. The clinical manifestations of CAH are varied and depend, in large part, on the extent of aldosterone or cortisol deficiency. In addition, in some forms of CAH, adrenocortical precursors accumulate to high concentrations and may cause signs and symptoms, such as hirsutism, hypertension, and menstrual irregularities. The phenotypic presentation of CAH fits into 3 main categories: (1) severe disease with adrenal insufficiency in infancy with or without virilization and salt wasting (classical CAH), (2) milder disease that manifests in adolescence or adulthood (nonclassic CAH), and (3) clinically inapparent disease (cryptic CAH).

The most common form of CAH results from deficiency of the enzyme 21-hydroxylase (encoded by the gene CYP21A) and is often divided into 3 phenotypes: salt wasting, simple virilizing, and nonclassic. Deficiency in 21-hydroxylase accounts for approximately 90% of CAH cases. Some infants go into salt wasting crisis within the first few days of life and die if untreated. Other than defects in 21-hydroxylase, the next most common CAH genetic defects are due to mutations in 11-beta-hydroxylase (gene = CYP11B1) or 17-alpha-hydroxylase (gene = CYP17). 11-beta-hydroxylase deficiency is most common in people of Iranian-Jewish or Moroccan descent.

Severe forms of CAH, if unrecognized and untreated, can be fatal due to salt wasting, dehydration, hyponatremia, and hyperkalemia. Classic CAH is often diagnosed in neonates or infants due to ambiguous genitalia, virilization, and salt wasting. Nonclassical CAH may be recognized in puberty in girls due to virilization or oligomenorrhea.

As of 2009, all 50 states in the United States, as well as 12 other countries, screen for CAH in newborn screening programs. These programs typically assay 17-hydroxyprogesterone (17-OHP) in infant blood spots on filter paper cards. The follow-up of positive 17-OHP varies regionally.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Many infants present for CAH work-up due to a positive newborn screening assay for 17-OHP. In these cases, regional protocols are recommended. Minimally elevated 17-OHP levels might trigger a second-tier analysis from the same blood spot card. Moderately elevated 17-OHP may warrant a follow-up filter paper specimen. Infants with high 17-OHP levels and signs of adrenal insufficiency (e.g., shock) require urgent evaluation and measurement of serum electrolytes and determination serum 17-OHP concentrations by a confirmatory method, such as liquid chromatography/tandem mass spectrometry (LC/MS/MS). A pediatric endocrinologist should be consulted for evaluation and treatment.

The workup of CAH in older children or adults is typically to obtain an early morning baseline serum 17-OHP in patients with signs and symptoms compatible with CAH (e.g., virilization, oligomenorrhea). The second step is to obtain a complete adrenocortical profile after a cosyntropin test. This helps distinguish 21-hydroxylase deficiency from other enzyme defects. Referral to a pediatric endocrinologist is recommended.

Genetic diagnosis currently does not have a major role in CAH other than to work-up patients whose cosyntropin stimulation profile results are equivocal or for genetic counseling.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

The diagnostic utility of 17-OHP is limited in first 2 days of life, when 17-OHP levels are normally high. The interpretation of newborn screening is also challenging in premature, sick, or stressed infants, as there are no established reference ranges for 17-OHP for these populations. There are also idiopathic false negatives for CAH in newborn screening methods. Lastly, treatment with steroids can have major impact on 17-OHP and other adrenocortical steroid precursors. Failure to recognize prior treatment with steroids can lead to misinterpretation of lab results, either in baseline laboratory studies or following cosyntropin administration.

What Lab Results Are Absolutely Confirmatory?

The gold standard for diagnosis of CAH is a cosyntropin stimulation test. However, this is often not practical in an infant presenting in adrenal crisis. Genetic testing can also specifically identify disease-causing mutations, although this approach is not yet widely used.

Additional Issues of Clinical Importance

CAH may go initially unrecognized if there is failure to thoroughly examine the newborn to rule out genital ambiguity. Newborn screening for 17-OHP also misses some rare, lethal forms of adrenal dysfunction in newborns, such as steroidogenic acute regulatory protein (STaR) deficiency or adrenal hypoplasia congenital. Finally, the large volume of newborn screens performed inevitably include some cases in which incorrect clinical contact information is provided, leading to potential delay in notifying clinicians of positive results.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Factors that may produce clinical errors include:

Mistakes can be made particularly in the work-up of late onset CAH. Practitioners unfamiliar with CAH may order inappropriate tests, such as 21-hydroxy antibodies (useful in work-up of autoimmune adrenal disease but not CAH).

The units of 17-OHP in newborn screens are generally ng/mL. However, many quantitative 17-OHP assays use ng/dL. Confusion of units can lead to misinterpretation.

The relatively high rate of false positives on newborn screens for 17-OHP (approximately 1%) can lead to complacency and slowness in following up on positive screens.

Failure to recognize prior treatment with steroids can lead to misinterpretation of laboratory results.